FIELD OF THE INVENTION:
The present patent invention pertains to formulations that ef'f ectively control the release of
oxcarbazepine and its derivatives for once-daily dosing. Specifically, the invention relates to
sustain release of the drug over an extended period, resulting in a consistent
pharmacological effect when administered orally once or twice a day.
BACKGROUND OF THE INVENTION: .
Oxcarbazepine is a benzodiazepine drug that has been enlisted overall as an antiepileptic
drug. It is supported for use as an assistant or monotherapy for the treatment of halfway
seizures and summed up tonic-clonic seizures in the two grown-ups and youngsters. The as
of now accessible quick delivery (IR) definition of oxcarbazepine, advertised as Trileptal'",
requires two times day to day dosing to control epileptic seizures successfully. Nonetheless,
these prompt delivery definitions can cause fast and sharp expansions in plasma drug focus,
prompting secondary effects and making various day to day dosing important to keep up
with restorative levels of the medication in the body.
Once-daily controlled-release (CR) dosage forms have significant clinical benefits, including
improved therapeutic efficacy and reduced side effects, and significantly improve patient·
compliance. However, the development of sustained-release dosage forms for these drugs
is significantly hampered by the fact that oxcarbazepine and its derivatives are poorly
soluble in water. Although sustained-release dosage forms have been described in the art,
these preparations have limited solubility and bioavailability for once-daily administration.
To meet the therapeutic requirements of the patient, customized drug release profiles are
required. Examples of these profiles include sigmoidal release patterns with an initial slow
release followed by a fast release followed by a slow release ·until the drug is released
completely from the dosage form. In the prior art, oxcarbazepine sustained-release
formulations and derivatives have been described, but no sigmoidal release profiles have
been observed. Take for instance Katzhendler et al. describes sustained-release delivery
systems for carbamazepine and its derivatives with zero-order release profiles made
possible by hydrophobic excipients and high molecular weight hydroxypropyl methyl
2
cellulose (HPMC). Franke and co. discloses sustained-release formulations of oxcarbazepine
that are suitable for once-a-day administration and are characterized by the release of 55%.85%
of the drug in 15 minutes and up to 95% in 30 minutes. However, these preparations
have limited solubility and bioavailability of the drug .
•
Even though the prior art has shown that oxcarbazepine and its derivatives can be .taken
once a day in sustained-release formulations, the drug's solubility and bioavailability from
these formulations <:~re still not optimal. Moreover, the earlier workmanship neglects to give
direction on the most proficient method to plan details that show a sigmoidal delivery
design, which can be helpful for accomplishing the ideal remedial impact while limiting
incidental effects.
Summary of the invention:
To meet the patient's therapeutic needs, this invention aims to provide controlled-release
oxcarbazepine formulations that can be taken once daily. The composition's goal is to
increase oxcarbazepine and its derivatives' bioavailability without triggering toxic "spikes" in
blood drug concentration. Furthermore, the creation means to keep the blood
centralization of the medication inside the restorative window and limit the change
between the Cmax and Cmin, which is ordinary of numerous quick delivery and supported
discharge arrangements.
The development accomplishes these targets using plans that incorporate both dissolvability
improving specialists and delivery advancing specialists. These definitions are portrayed by
discharge profiles that meet the necessities for once-a-day·organization. One more method
for accomplishing these targets is through the blend of a variety of units with various
delivery profiles in a single measurements unit. This can be accomplished by utilizing
minipellets, granules, or tablets that can be blended in a specific proportion •to give a
measurements structure that meets the above-expressed restorative targets.
Multi-facet tablets are likewise important for this innovation. The drug may be released at a
different rate at each layer of the tablet than it is released at another layer. The layers might
be covered.
3
In comparison to other formulations, the compositions of this invention offer a number of
advantages. For instance, they provide less variation between Cmax and Cmin during
treatment, which improves the therapeutic profile. The creations additionally offer
decreased aftereffects, worked on persistent consistence, and further developed
bioavailability of the medication. In general, this invention offers a novel and efficient
method for administering oxcarbazepine that meets the patient's therapeutic requirements.
Objectives of the present invention:
It is ari essential goal is to give controlled discharge plan of oxcarbazepine for once per day
organization.·
It is one more level headed of the current development to work on the bioavailability of
oxcarbazepine and subordinates thereof.
Another goal of the present invention is to meet the therapeutic needs of the patient
without causing toxicity-causing sudden increases in the drug's blood concentration.
Keeping the drug's blood concentration within the therapeutic range is another goal of the
present invention.
Reduce the variation between the maximum and minimum blood drug concentration, which
is common in both immediate-release and sustained-release formulations, is yet another
goal ofthe present invention.
Description of the invention:
Those talented in the craftsmanship will know that the current exposure· is dependent upon
varieties and alterations other than those explicitly depicted. It should be understood that
all of these variations and modifications are included in the current disclosure. In addition,
all of the process steps and product features mentioned or indicated in this
specification-individually or collectively-as well as any and all combinations of any and all
of these steps and features are included in the disclosure.
The particular embodiments that are presented here are only meant to serve as examples
and do not limit the scope of the present disclosure ..
4
The essential target of this innovation is to ·make controlled-discharge details of
oxcarbazepine that are· proper for once-a-day organization. By incorporating solubility~
enhancing excipients and/or release-promoting agents into the formulations, an additional
goal is to improve the bioavailability of oxcarbazepine and its derivatives.
The formulations of oxtarbazepine are intended to have sigmoidal release profiles, which
include a slow initial release, a rapid subsequent release, and yet another period of slow
release. In order to verify their usefulness, human pharmacokinetic studies tested these
release profiles. The formulations were enhanced by incorporating solubility enhancers
and/or release-promoting excipients on the basis of the findings of these studies.
After that, the enhanced formulations were put through their paces in canine models, and
the results showed that the bioavailability of oxcarbazepine was significantly higher than · ·
that of formulations that did not contain .release-enhancing or solubility-enhancing
excipients.
This innovation intends to work on· the solvency and bioavailability of ineffectively
dissolvable medications, for example, oxcarbazepine by integrating dissolvability improving
specialists into the plans. By upgrading the solvency of oxcarbazepine, the medication's
bioavailability is improved, prompting ·better remedial execution. The development
proposes a mix of solvency and delivery advancing specialists, including pH-subordinate
polymers known as intestinal polymers, which disintegrate at pH values higher than 4.0
however stay insoluble at lower pH values. When the enteric polymer and solubilizer are
placed in an aqueous niedium with a pH greater than 4.0,. the resulting structure is porous.
This construction expands the surface region between the fluid medium and the
ineffectively solvent medication, which upgrades the effectiveness of the solubilizer(s),
bringing about expanded dissolvability and delivery paces of the medication, working on its
accessibility for foundational assimilation in patients.
5
Ionic and non-ioriic surfactants, complexing agents, hydrophilic polymers, pH modifiers like
acidifying and alkalinizing agents, and molecules that increase the solubility of poorly
soluble drugs through molecular entrapment are examples of the solubility enhancers in the
formulation. It is possible to utilize multiple solubility enhancers simultaneously. All
intestinal polymers that stay in one piece at pH values lower than around 4.0 and break
down at pH,values higher than 4.0, ideally higher than 5.0 and generally ideally around 6.0,
are viewed as helpful as delivery advancing specialists.
Instances of reasonable pH-delicate intestinal polymers incorporate cellulose acetic acid
derivation phthalate, cellulose acetic acid derivation succinate, methylcellulose phthalate,
ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinylbutyrate acetic acid
derivation, vinyl acetic acid derivation maleic anhydride copolymer, styrene-maleic
monoester copolymer,· methyl acrylate-methacrylic corrosive copolymer, and methacrylatemethacrylic
corrosive octyl acrylate copolymer. These polymers can be utilized on th.eir own
or in conjunction with other polymers not previously mentioned. The pharmaceutically
acceptable methacrylic acid copolymers, anionic polymers based on methacrylic acid and
methyl methacrylate with a mean molecular weight of approximately 135000, are the
preferred enteric polymers. The proportion of free carboxyl gatherings to methyl-esterified
. carboxyl gatherings in these copolymers can go from 1:1 to 1:3, for instance, around 1:1 or
1:2. These copolymers are sold under the business trademark Eudragit"', like the Eudragit L
series (e.g., Eudragit L 12.5'M, Eudragit L 12.5P'M, Eudragit LlOO' .. , Eudragit L 100-55"',
Eudragit L-30D'M, Eudragit L-30 D-55'") and the Eudragit S series (e.g., Eudragit S 12.5' .. ,
Eudragit S 12.5P' .. , Eudragit 5100' .. ). It is important that the delivery advertisers are not
restricted to pH-subordinate polymers and that other hydrophilic parti.cles that disintegrate
rapidly and make a permeable design can likewise be utilized for a similar reasol).
The amount of the agent that helps the drug release from the body can be anywhere from
10 percent to 90 percent of the total weight of the dosage unit. The preferred amount is
between 20 and 80 percent, and the most preferred amount is between 30 and 70 percent.
This release-promoting agent can be a'dded to the medication before or after granulation. It
can be dry, dispersed, or dissolved in a suitable solvent before being distributed during
granulation.
6
Solubilizers like sodium docusate, sodium Iaury! sulfate, sodium stearylfumarate, low
molecular weight polyvinyl pyrrolidone, low molecular weight hydroxypropyl methyl
cellulose, cyclodextrins, and pH modifying agents like citric acid, fumaric acid, tartaric acid,
hydrochloric acid, meglumine, and sodium hydroxide are preferred in the invention to These
solubilizing agents typically account for anywhere from one percent to eighty percent of the
dosage form's weight; the most common range is one percent to sixty percent, with a
preference for one percent to fifty percent. Before the medication is granulated, either dry
or wet solubilizers can be added. They can also be added after the other ingredients have
been granulated or processed. Solubilizers can be sprayed as solutions with or without a
binder during granulation.
Controlled-release formulations of oxcarbazepine that release the drug at different rates in
the gastrointestinal (GI) tract are provided by the present invention in another embodiment.
The essential goal of this innovation is to foster a medication conveyance framework that ·
can deliver the medication at a low rate at first, trailed by a generally expanded rate,
consequently giving a medication discharge profile portrayed by a quick delivery, trailed by
a changed delivery like broadened discharge (XR) or deferred discharge (DR). A pattern. like
this can help keep the drug's therapeutic concentration within the therapeutic window and
extend the time it takes. for the body to maintain an effective drug level.
The controlled-discharge drug sythesis of oxcarbazepine expects to give consistent state
blood levels of MHO, a functioning metabolite of oxcarbazepine, at a convergence of around
2 ~g/ml to around 10 ~g/ml. In the favored epitome, consistent state blood Cmax levels of
MHO fall in the scope of around 6 ~g/ml to around 10 ~g/ml, and Cmin levels of MHO fall in
the scope of around 2 ~g/ml to around 5 ~g/ml. The controlled-discharge detailing of
oxcarbazepine is intended to lessen change among • Cmax and Cmin during treatment,
bringing about a superior restorative profile, decr~ased incidental effects, worked on
understanding consistence, and further developed bioavailability of the medication.
The ideal medication discharge design in this creation is accomplished by utilizing "grid"
polymers that hydrate and swell in watery media like organic liquids .. During drug release,
these polymers form a uniform matrix structure that acts as a carrier for the drug, solubility
enhancers, and release promoters. The drug releases slowly (lag phase) during the initial
matrix polymer hydration phase. The pH-dependent release promoters leak out of the
7
polymer once it is fully hydrated and swollen, increasing matrix porosity and accelerating
drug release. The drug diffusion through the hydrated polymer gel determines the constant
rate of drug release ..
The delivery versus time bend is portrayed by something like two inclines: one slope for the
lag phase, where the rate of drug release is low, and a second slope for the faster phase.
The rate at which the drug is eliminated from the body can be adjusted to match the slope
of the rising portion of the release vs. time curve. Swell able polymers can be used alone or
in conjunction with binders like gelling and/or network-forming polymers to create the
desired release profile.
Hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose
(HEC), methylcellulose (MC), powdered cellulose, cellulose acetate, sodium
carboxymethylcellulose, calcium salt of carboxymethylcellulose, and ethylcellulose are all
examples of water-swellable, matrix-forming ·polymers used in the present invention.
Different polymers thaf can be utilized incorporate .alginat~s, gums like guar and thickeners,
cross-connected polyacrylic corrosive subsidiaries like Carbomers, carageenan, polyvinyl
pyrrolidone and its subordinates, for example, crospovidone, polyethylene oxides, and
0 0
polyvinyl liquor. Swellable polymers that are preferred are cellulosic compounds, with
HPMC being the most preferred among these.
The formulation's swellable polymer content can range anywhere from one percent to fifty
percent by weight, most preferably from five percent to forty percent by weight, and most
preferably from five percent to twenty percent by weight. In addition to being sprayed
during granulation and dispersed in organic solvents or hydro-alcohols, the swellable
polymers and binders .can be incorporated into the formulation either before or after
granulation.
Preparing oxcarbazepine formulations that combine multiple modified-release "units," each
of which is prepared according to one or more of the dosage forms discussed above, to
create a unique release profile is another aspect of the invention. Minipellets, granules,
tablets, and other forms of modified-release products are examples. each with their own
distinct release profiles, which can be combined in a particular ratio to produce a dosage
form that meets the therapeutic goals. On the other hand, various changed discharge units
might be framed into multi-facet tablets, with each layer delivering the dynamic build at a
8
rate that is not the same as the pace of arrival of the dynamic fixing from another layer.
Each layer may alternatively be covered with controlled-discharge polymers. Any or all
possible combinations of immediate release (IR), delayed release (DR), and extended release
(XR) formulations can be seen in the release profiles of the combination dosage forms.
Coating can optionally be applied to tablets, granules, pellets, or each layer of a single
tablet.
The dosage unit's hydration rate when exposed to water or other aqueous media can be
altered with the help of a variety of hydrophobic excipients. These exi:ipients alter the active
agent's release and. delay the dosage unit's wetting. Reasonable hydrophobic excipients
incorporate, · yet are not restricted to, glycerylmonstearate, combinations of
glycerylmonostearate and glycerylmonopalmitate (Myvaplex, Eastman Fine Substance
Organization), glycerylmonooleate, a combination of mono, di and tri-glycerides (ATMUL
84S),. glycerylmonolaurate, glycerylbehenate, paraffin, white wax, long chain carboxylic
acids, long chain carboxylic corrosive esters and long chain carboxylic corrosive alcohols.
Saturated straight chain acids like n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic
acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic
acid, arachidic acid, behenic acid, montanic acid, and melissic acid contribute to the success
of the invention. Unsaturated monoolefinic straight chain monocarboxylic acids like oleic
corrosive, gadoleic ·corrosive, and erucic corrosive are additionally valuable. Moreover,
unsaturated (polyolefinic) straight chain monocarboxylic acids, for example, linoleic
corrosive, linolenic corrosive, arachidonic corrosive, and behenolic corrosive are helpful. .
Additionally, branched acids like diacetyl tartaric acid can be used.
Long chain carboxylic acid esters, such as glycerylmonopalmitates (Myvaplex 600, Eastman
Fine Chemical Company), glycerylmonolinoleate,
glycerylmonogadoleate, glycerylmonogadoleate,
glycerylmonogadoleate, glycerylmonogado
glycerylmonooleate,
glycerylmonogadoleate,
Polymers, other excipients, and the active ingredient are typically combined with a
granulating fluid, such as water, an alcohol-water mixture, or anhydrous alcohol, during the
manufacturing process of oxcarbazepine-containing pharmaceuticals. To produce matrix
9
granules or tablets, this mixture can then be processed using wet granulation, slugging,
roller compaction, or direct compression.
Mixers, high shear granulators, and fluid bed granulators are some of the granulating tools
used. in wet granulation to add the granulating fluid to the mixture. The subsequent wet
granules are then dried utilizing gear like liquid bed dryers, broilers, microwave dryers, or
via air-drying. The granules can be tableted on a tablet press or mixed with other excipients
and milled to a specific particle size distribution after being dried. Granules can also be
packaged in sachets for use as sprinkles.
To make tableting easier, other excipients like talc, magnesium stearate, or cabosil can be
added, and dyes can be included in the formulation. Greases, for example, magnesium
stearate, calcium stearate, or polyethylene glycol, can likewise be added to guarantee
appropriate tableting. How much oil utilized regularly goes from 0.1 to 20 weight percent of
the sythesis.
There are many ways to make pellets, granules, and tablets. For tablets, the dynamic fixing
can be compacted from a straightforwardly compressible mix or pre-framed granules, and
might be covered. Granules can be coated or not by using high shear granulation or fluid
bed processing. Pellets can be made by drug layering on latent transporters or by
expulsion/spheronization processes, and might be covered. Capsules can be made from
coated pellets and granules. The assembling steps associated with these cycles are notable
to those gifted in the craftsmanship.
The present invention makes it possible to make drug products in pelletized forms that are
simple to put. into capsules or sachets for applying by sprinkles. Every pellet is comprised of
the medication, swellable polymers, and other excipients that guide in the handling of the
plan. There are different strategies known to those gifted in the workmanship to get ready
pelletS, including expulsion/spheronization and roller compaction (slugging).
The drug is mixed with other excipients and swellable polymers, like cellulosic polymers, in
the extrusion/spheronization method. After that, a high shear granulator is used to
granulate the mixture into a wet mass. Spherical pellets are produced by spheronizing the
10
wet mass through an extruder ;;tnd a spheronizer. After that, either a fluid bed processor or
an oven is used to dry the pellets. The dried pellets can be encapsulated without further
processing or further processed.
A once-a-day pharmaceutical formulation containing oxcarbazepine, a homogeneous matrix
containing a matrix-forming polymer, at least one solubility-enhancing agent, and at least
one release-promoting agent containing a pH-dependent soluble polymer are the focus of
the present invention. Cellulosic polymers, alginates, gums, cross-linked polyacrylic acid,
carageenan, polyvinyl pyrrolidone, polyethylene oxides, and polyvinyl alcohol are among the
matrix-forming polymers. Surface active agents, complexing agents, cyclodextrins, pHmodifying
agents, and hydration promoting agents are all options for the solubilityenhancing
agent. The delivery advancing specialist might contain a polymer having pHsubordinate
· solvency, for example, cellulose acetic acid derivation phthalate or Eudragit
ll00-55. The agent that increases the solubility of oxcarbazepine may be present in a
quantity ranging from 1% to 80% by weight of the formulation, while the release promoting
agent may be present in a quantity ranging from 10% to 90% by weight. With Cmax levels of
monohydroxy derivative of oxcarbazepine in the range of approximately 6 g/ml to
approximately 10 g/ml and Cmin levels of monohydroxy derivative of oxcarbazepine in the
range of approximately 2 g/ml to approximately 5 g/ml, the formulation may. be able to
produce a steady state blood level of about 2 g/ml to about 10 g/ml. The plan might be as
pellets, tablets, granules or cases, and may incorporate wax, grease, and other excipients as
required. A particular illustration of the plan might incorporate HPMC and polyvinyl
pyrrolidone as network framing polymers; oxcarbazepine's solubility is improved by sodium
lauryl sulfate, and the release-promoting agent is Eudragit L100-55 (Methacrylic Acid-Ethyl
Acrylate Copolymer (1:1)).
It ought to be noticed that except if expressly characterized in any case, all specialized and
logical terms utilized in the creation have a similar importance as generally figured out by
one of customary expertise in the craftsmanship. In addition, the present invention
incorporates by_ reference all publications, patent applications, patents, and other
references cited in it. The present specification, including its definitions, will prevail in the
event of a- disagreement between it and any of the cited references. The invention's
II
materials, procedures, and examples are provided only as examples and are not intended to
be restrictive.
12
We claim:
1. A daily pharmaceutical formulation that includes:
oxcarbazepine, a homogeneous matrix consisting of a matrix-forming polymer,
oxcarbazepine, at least one solubility-enhancing agent, and at least one release-promoting
agent consisting of a pH-dependent soluble polymer ·
2. The formulation as claimed in claim 1, wherein the framework shaping polymer chose from
the gathering comprising of cellulosic polymers, algi nates, gums, cross-connected polyacrylic
corrosive, carageenan, polyvinylpyrrolidone, polyethylene oxides, and polyvinyl liquor.
3. The formulation as claimed in claim 1, wherein the dissolvability upgrading specialist is
chosen from the gathering comprising of surface dynamic specialists, complexing specialists,
cyclodextrins, pH altering specialists, and hydration advancing specialists.
4. The formulation as claimed in claim 1, wherein the Polymers with pH-dependent solubility,
such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate,
ethylhydroxycellulose phthalate, polyvinylacetate phthalate, polyvinyl butyrate acetate, vinyl
acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, and Eudragit
ll00-55 (Methacrylic
5. The formulation as claimed in claim 1 to 4, wherein the Sodium docusate, sodium lauryl
sulfate, sodium stearylfumarate, polyethylene oxide (PEO) modified sorbitan monoesters,
fatty acid sorbitan esters, polyethylene oxide-polypropylene oxide-( poly( ethylene oxide))
block copolymers, or combinations thereof;
wherein hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), methylcellulose. (MC), powdered cellulose, cellulose acetate,
sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, and ethylcellulose
are the cellulosic polymers chosen from the group.
6. The formulation as claimed in claim 1, wherein the release promoting, agent present in
amounts ranging from 10% to 90% by weight and the agent that increases oxcarbazepine's
solubility present in amounts ranging from 1% to 80% by weight.
7. The formulation as claimed in claim 1, wherein the oxcarbazepine is viable to deliver a
consistent state blood level of monohydroxy subordinate of oxcarbazepine in the scope of
around 2 llg/ml to around 10 llg/ml.
8. The formulation as claimed in claim 1, wherein the Cmax levels of the monohydroxy
derivative of oxcarbazepine ranging from approximately 6 to approximately 10 g/ml and
Cmin levels of the monohydroxy derivative of oxcarbazepine ranging from approximately 2
to approximately 5 g/ml, respectively.
9. The formulation as claimed in claim 1, wherein the formulation Pellets, tablets, granules, or
capsules.
10. The formulation a·s claimed in claim 1 to 9, wherein the Beeswax, camuba wax, cetyl alcohol,
glyceryl stearate, glycerylpalmitate, and stearyl alcohol are all options for the wax in the
formulation described in claims 1 through 9.. ·
wherein the lubricant is selected from the following: stearic acid, polyethylene glycol,
leucine, glycer'ylbehenate, sodium stearylfumarate, hydrogenated ve~etable oils, waxes,
calcium stearate, zinc stearate, and magnesium stearate.
where the pH-dependently solubilized polymer persists at pH values below 4 and dissolves
at pH values above 4; and
wherein HPMC.and polyvinylpyrrolidone are polymers that form matrices; oxcarbazepine's
solubility is improved by sodium lauryl sulfate, and the release-promoting agent is Eudragit
ll00-55 (Methacrylic Acid-Ethyl Acrylate Copolymer (1:1)).